Therapeutic calcium phosphate particles in use for aesthetic of cosmetic medicine, and methods of manufacture and use

ABSTRACT

Calcium phosphate (“CAP”) particles for use in cosmetic, nutraceutic or aesthetic medicine. The particles may be used as carriers for cosmetic, nutraceutic or a factors, as controlled release matrices for the material, and as fillers in cosmetic treatments. The particles may be applied topically or injected or by any other appropriate delivery method.

BACKGROUND OF INVENTION

This application claims the benefit of U.S. patent application Ser. No.60/623,958, filed Nov. 1, 2004, the entire contents of which are herebyincorporated by reference.

1. Field of the Invention

The present invention relates to novel calcium phosphate core particlesfor use in aesthetic medicine, to methods of making them, and to methodsof using them in corrective or cosmetic surgery, as filler, for thesustained release of cosmetic medicines, and as a delivery vehicle forpharmaceutical agents, nutraceuticals, growth factors, and/or tissuerepair chemicals and biochemicals.

2. Description of Related Art

Nanometer scale particles have been proposed for use as carrierparticles, as supports for biologically active molecules, such asproteins, and as decoy viruses. See U.S. Pat. Nos. 5,178,882; 5,219,577;5,306,508; 5,334,394; 5,460,830; 5,460,831; 5,462,750; and 5,464,634,the entire contents of each of which are hereby incorporated byreference.

The particles disclosed in the above-referenced patents, however, aregenerally extremely small, in the 10-200 nm size range. Particles ofthis size are difficult to make with any degree of consistency, andtheir morphology is not described in any detail. None of these patentsdisclose the use of nanoparticles as sustained release matrices.Furthermore, these patents do not disclose the use of calcium phosphateparticles as either adjuvants or delivery vehicles for aestheticmedicine or treatments.

There has been a suggestion in the literature to use calcium phosphateparticles as vaccine adjuvants, but calcium phosphate particles havegenerally been considered an unsuitable alternative to other adjuvantsdue to inferior adjuvanting activity. See, e.g., Goto et al., Vaccine,vol. 15, no. 12/13 (1997). Moreover, the calcium phosphate evaluated wastypically microparticulate (>1000 nm diameter) and possessed a rough andoblong morphology, in contrast to the core particles of the presentinvention.

Therefore, an important need remains for calcium phosphate coreparticles useful as core materials or carriers for biologically activemoieties that can be produced simply and consistently. A further needremains for calcium phosphate core particles that can be effectivelyused as adjuvants and delivery vehicles for aesthetic medicines andtreatments, and as controlled release matrices for use in cosmetic,nutraceutic, or aesthetic applications.

The inventor's issued patent and pending patent application disclosemany varieties of CAP particles and their methods of use. U.S. Pat. No.6,355,271, which is hereby incorporated by reference, discloses theinventor's novel therapeutic calcium phosphate particles and methods oftheir manufacture and use. Further, pending U.S. patent application Ser.Nos. 09/794,576, 09/932,538, 09/932,503, 10/306,062, and 10/824,097disclose other compositions and uses of the inventor's calcium phosphateparticles. Each of these applications is hereby incorporated byreference.

SUMMARY

The present invention relates to novel calcium phosphate (“CAP”) coreparticles, to methods of making them, to methods of using them incosmetic, nutraceutic, or aesthetic medicine, as cores or carriers forbiologically active material, as controlled release matrices forbiologically active material, and as fillers for aesthetic treatments.The core particles preferably have a diameter between about 200 nm andabout 4000 nm, more particularly between about 300 nm and about 1000 nm,and they have a substantially spherical shape and a substantially smoothsurface.

The present invention also relates to the novel calcium phosphate coreparticles having a material coated on the surface of the core particles,and/or dispersed or impregnated within the core particles, to methods ofmaking them, and to methods of using them.

The present invention also relates to combinations of this novel coreparticle having at least a partial coating of a surface modifying agentor a surface modifying agent impregnated therein or both. If a cosmetic,nutraceutic, or aesthetic material is at least partially coated on theparticle, the material may be optionally attached to the particle by thesurface modifying agent, which acts as a biological “glue,” such ascellobiose or polyethylene glycol (PEG), although other biological gluesare usable with the present invention.

The invention also relates to combinations of this novel core particlewith cosmetic, nutraceutic, or aesthetic agents integrated into the coreparticle, forming a controlled release matrix that releases the materialinto a patient over time.

A further embodiment relates the use of the novel calcium phosphateparticles as a stand-alone filler in cosmetic, nutraceutic, orreconstructive surgery. The calcium phosphate particles may be injectedintramuscularly or intratissue and may be used as a solid or semi-solidbase, or as a support foundation. Various uses for the injection ofcalcium phosphate particles include use as a filler in an effort tosmooth skin and reduce wrinkles or other unwanted skin irregularities.Other embodiments of the invention relate to a combination of theparticles and a microdermabrasion component for use in treating thesurface of a patient's skin. Further embodiments relate to the use of acombination of the particles and another skin treatment agent that canbe applied topically, applied to mucosal surfaces of the body, orinjected.

In a specific embodiment, the invention relates to methods of providingcosmetic, nutraceutic, or aesthetic agents or medicines (which aredescribed in more detail below and will be referred to collectively as“aesthetic factors”) to patients in need thereof by administration ofthe novel core particles in combination or in conjunction with agentuseful in cosmetic, nutraceutic, or aesthetic applications, wherein theagent is at least partially coated on the core particle and/orintegrated therein. It is thought that the calcium phosphate coreparticles of this embodimentmay significantly increase the efficacy ofthe agents with which they are administered, by enhancing themagnitudes, qualities, and/or durations of the patient's responses. Thisextended bioavailability may reduce the amount of agent needed to attainthe desired effect, thus resulting in a decrease in both cost and safetyconcerns. The calcium phosphate particles may also improve the “halflife” or stability of the “active” or aesthetic factor that isco-administered. The calcium phosphate particles of this embodiment maybe provided to the patient by any method previously described in theinventor's patent applications, including topical application, tomucosal surfaces of the body, and delivery through injection.

In another embodiment, the invention also relates to the use of theinventor's novel calcium phosphate particles as a delivery vehicle incosmetic, nutraceutic, or aesthetic procedures. The calcium phosphateparticles of the present invention may be delivered topically,transdermally, intradermally, subdermally, subcutaneously,transmucosally, or through intramuscular or intratissue injection.Examples of agents which may be delivered through the invention's novelcalcium phosphate particles include vaccines, anti-pain medications,anti-inflammatory medications, anti-cancer medications and antibiotics,anti-acne treatments, pore reducing treatments, sun-damage treatments,eczema or other skin condition treatments, broken capillary treatments,vitamins, minerals, herbs, muscle relaxants, growth factors, tissuerepair chemicals, blockers of muscle contraction, in combination withother known fillers, and/or biochemicals. Examples of such agentsinclude, but are not limited to, vitamins, minerals, nutrients,epidermal growth factors, fibroblast growth factor, collagen,Interleukin-1, and tumor necrosis factor. Alternatively, if preferred,agents such as anti-epidermal growth factor, anti-fibroblast growthfactor, anti-IL-1, and anti-tumor necrosis factor may be delivered.

The present invention also relates to methods of treating physiologic,metabolic, cosmetic and aesthetic medical conditions by administeringeffective amounts of the calcium phosphate particles either as “standAlone” entities, or, in combination with cosmetic medicines to a patientin need thereof. The therapeutic compositions of the present inventionare highly stable and may exhibit enhanced bioavailability, improvedstability, efficacy, or increased “half life” after in vivoadministration. These therapeutic compositions also exhibit preferablebiodynamics including controlled release of cosmetic, nutraceutic, andaesthetic agents. . . . The present invention also relates to methods ofpreparing the novel calcium phosphate core particles described above,such as the core particles for use individually, the core particleshaving material at least partially coated on the surface, and the coreparticles having material impregnated therein.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

The present invention relates generally to novel calcium phosphate coreparticles, to methods of making them, and to methods of using the coreparticles as adjuvants, for functional enhancement of drugs andtherapeutic factors, or as delivery vehicles for nutraceutic andaesthetic treatments, as controlled release matrices for aesthetictreatments, and as “stand-alone” fillers for use in cosmetic treatments.The present invention also relates to the novel calcium phosphate coreparticles having a desired material at least partially coated on thesurface of the core particles, or dispersed or impregnated within thecore particles, to methods of making them, and to methods of using them.Non-limiting examples of a suitable material to be at least partiallycoated on the surface of the core particle or impregnated thereininclude aesthetic factors that are intended to treat wrinkles and/orskin imperfections, to enhance skin elasticity, moisture, and/orappearance; to deliver skin-enhancing minerals and vitamins; to act as afiller; to abrade the surface of the skin such as dermabrasion orexfoliation; to provide nourishment (for example, in the form ofnutrients or vitamins, minerals or growth factors, all collectivelyreferred to as “nutraceuticals”) to underling skin cells; to treat otherskin conditions such as eczema, acne, rosacea, moles, wrinkles, and soforth.

The core particles of the present invention may optionally have at leasta partial coating of a surface modifying agent, which may help adherethe above-mentioned material to the core particle, or may have a surfacemodifying agent impregnating the particle, or both. A preferred form ofsuch an agent is polyethylene glycol or other mono- or disaccharides.

One embodiment of the present invention relates to calcium phosphatecore particles suitable for delivering, adjuvanting or enhancing therespective chemical and/or biological functions of variousnutraceuticals, and cosmetic or aesthetic factors, the particles beingadministrable in their uncoated state. The core particles are alsosuitable for use as supports for cosmetic, nutraceutic, or aestheticagents and for providing a controlled or sustained release matrix forsuch products and medicines. Another embodiment of the present inventionrelates to the use of the calcium phosphate particles as a filler , inother words, the particles may be delivered as “stand-alone” particles.

The calcium phosphate core particles of the present invention have anaverage particle size between about 200 nm and about 4000 nm, moreparticularly, between about 200 nm and about 2000 nm. For theapplications described herein, an average particle size of between about200 nm and 1000 nm is sufficient and desirable. The core particles ofthe present invention have a morphology that is generally andsubstantially spherical in shape and a surface that is substantiallysmooth.

The term “substantially smooth” is used herein to mean essentially nosurface features or irregularities having a size of 100 nm or larger.The core particles may be faceted or angular and still fall within thisdefinition, as long as the facets do not contain many surfaceirregularities of the type described above. The term “substantiallyspheribal” is used herein to refer to particles that are substantiallyround or oval in shape, and includes particles that are unfaceted andsmooth, or that have very few facets, as well as particles that arepolyhedral having several or numerous facets.

In another embodiment, the core particles of the present invention canalso be at least partially coated with material, wherein the material isdisposed on the surface of the core particle and optionally held inplace by a surface modifying agent sufficient to bind the material tothe core particle without denaturing the material.

Surface modifying agents suitable for use in the present inventioninclude substances that provide a threshold surface energy to the coreparticle sufficient to bind material to the surface of the coreparticle, without denaturing the material. Example of suitable surfacemodifying agents include those described in U.S. Pat. Nos. 5,460,830,5,462,751, 5,460,831, and 5,219,577, the entire contents of each ofwhich are incorporated herein by reference. Non-limiting examples ofsuitable surface modifying agents may include basic or modified sugars,such as cellobiose, or oligonucleotides, which are all described in U.S.Pat. No. 5,219,577. Suitable surface modifying agents also inchidecarbohydrates, carbohydrate derivatives, and other macromolecules withcarbohydrate-like components characterized by the abundance of -OH sidegroups, as described, for example, in U.S. Pat. No. 5,460,830.Polyethylene glycol (PEG) is a particularly suitable surface modifyingagent.

The particles of this invention may be combined with any of the wrinkletreatments, skin fillers, dermal stimulators, topical treatments,vitamins and minerals, and/or vein therapy treatments described below,or any similar agents. (The examples provided in this application areintended to be non-limiting.) The particles may additionally oralternatively be delivered alone to act as a skin filler.

In a specific embodiment, the particles may be formed as described inExample 1, and if they are intended to be used as a carrier of anaesthetic factor, the composition (referred to in the Example and in thebelow descriptions as “an aesthetic factor”) may either be added to theformulation during particle formation so that it is at least partiallyimpregnated into the particles or it may be coated onto the particles,or a combination of both.

The below example provides only one way that can be used to make thecore particles of the present invention, and it should be understoodthat other methods can be provided and are considered within the scopeof this invention. Moreover, as previously stated, the examples ofmaterials that may form an aesthetic factor or that may be deliveredusing the particles of the present invention are provided merely asexamples, and it is intended that any other aesthetic treatments ormedicines may be delivered or adjuvanted using the described particles.

EXAMPLE

A 12.5 mM solution of CaCl₂ is prepared (for example, by mixing 1 to 2 gof CaCl₂ into 800 mL of sterile GDP water under aseptic conditions untilcompletely dissolved, and diluting it to 1 L, and then filtering). A15.625 mM solution of sodium citrate is then prepared (for example, bydissolving 0.919 g of sodium citrate into 200 mL of sterile GDP waterwith mixing using aseptic techniques and filtered). Then, a 12.5 mMsolution of dibasic sodium phosphate is prepared (for example, bydissolving 1.775 g sodium phosphate into 1 L of sterile GDP water withmixing using aseptic techniques and filtered). All solutions were storedat room temperature.

The calcium chloride solution is combined with the sodium citratesolution and thoroughly mixed. The sodium phosphate solution is thenadded with mixing. Turbidity appears as particles began to form. Incertain embodiments, the particles may be used by themselves (asfillers), which will be described in more detail below. In otherembodiments, an aesthetic factor (which is intended to be any aestheticfactor described in this application, as well any other aestheticfactors or components that may be used to treat skin or otherwiseenhance the skin's appearance) may be added during the formation ofthese particles. This is intended to form particles that have anaesthetic factor at least partially embedded therein.

In a further embodiment, an aesthetic factor is added to a solution ofparticles that have already been formed. In this instance, the abovesuspension is allowed to mix for several minutes and mixing may becontinued for about 48 hours under a laminar flow hood. Followingmixing, the particles may be sonicated on a high power setting for about30 minutes at room temperature. Following preparation, the particles mayalso be allowed to equilibrate for approximately seven days before use.

Cellobiose (or polyethylene glycol or any another biological “glue”) maythen be applied to the particles by suspending them in a solution of theglue added to the suspension of calcium phosphate particles, typicallyat a ratio of 1 mL of “glue” to 20 mL of particle suspension. Themixture is gently mixed and allowed to stand overnight. The at leastpartially coated particles are then contacted with a solution of anaesthetic factor.

I. Wrinkle Treatments

A first embodiment of the invention relates to calcium phosphateparticles as core carriers or adjuvants and delivered in combinationwith a wrinkle treatment, such as a muscle relaxant or a skin filler,which may be the aesthetic factor in the above example. Anotherembodiment relates to the particles delivered alone for use as a skinfiller. Facial lines and wrinkles are caused by the destruction of thesupport layer within the skin. Injectable treatments, such as Botox, canrelax underlying muscles and allow the skin to relax. Injectableimplants such as collagen and restylane replenish the skin's naturalsupport layer, smoothing facial lines and many types of scars. Suchtreatments are typically injected, although it is foreseeable that suchtreatments may also be delivered topically or otherwise at some point inthe future.

There are two different kinds of facial wrinkles—static and dynamic.Static wrinkles are the lines and folds that are on the face all thetime. Dynamic wrinkles are the lines that appear when there is musclemovement resulting in facial expressions (crow's feet, frown or foreheadlines). Botox® is designed to stop dynamic wrinkles. It prevents thenerves ending from communicating to the muscle to contract. Botox®, orBotulinum Toxin type A, is an FDA approved treatment that is injectedinto the muscles that cause lines and wrinkles. Commonly treated areasinclude frown lines between the eyebrows, wrinkles around the eyes, andhorizontal lines on the forehead. As the treated muscle weakens, theskin overlying the muscle also relaxes and wrinkles begin to soften.Botox (or any other muscle weakening component or composition) may beused as an aesthetic factor in the above example. Those of ordinaryskill in the art would be able to determine appropriate concentrationand dosage amounts.

Another type of wrinkle treatment is a skin filler. Botox® is not afiller. It will not fill or plump up lines or depressions in the skinthat are present the face is at rest. In order to improve deep setstatic lines, there are treatments, called “skin fillers,” that plump upthe lines. The delivery of the calcium phosphate particles describedherein can be used as a skin filler. They may be delivered alone, incombination with a pharmaceutically acceptable excipient, or incombination with another skin filler (examples of which are discussedbelow) to lessen fine lines around the eye area, forehead, around themouth, and any other skin surface. Without wishing to be bound to anytheory, it is believed that the calcium phosphate particles of thisinvention have skin filler action that is similar to that described forhyaluronic acid, collagen, and hydroxyapatite. However, by virtue of ourthe physicochemical characteristics (including size, chemicalcomposition, methods of manufacture, and biocompatibility) of theparticles of this invention, as well as its various routes ofadministration (e.g. topical, subcutaneous, intradermal, intramuscular,intraocular, etc), it is likely to have better functionalcharacteristics (such as no disfigurement of skin after use becauseparticles are generally less than 5 microns in surface diameter and areless likely to agglomerate or clump like the larger particulatefillers), as well as because of non-irritant effects, biocompatibility,non-allergy inducing effects, and longer half-life.

As mentioned, it is also possible to deliver the calcium phosphateparticles described above in connection with other skin fillers—with theparticles acting as a delivery vehicle, controlled or sustained releasemechanism, as an adjuvant, and/or as an additional skin filler. Forexample, collagen is commonly-used skin filler for treating wrinkles.Renewing the supply of collagen through injections can smooth faciallines, deep smile folds, and scars. It is also successful in enhancingthe lip line. Because it is a natural substance, collagen can beinjected beneath the skin's surface and it will not be rejected. Thistreatment typically provides an immediate and visible difference in theappearance of the skin. Injected collagen and fat are primarily used toimprove the appearance of the skin's texture and contour, restoring amore youthful looking appearance. They can help fill out deep facialwrinkles, creases and furrows, “sunken” cheeks, skin depressions andsome types of scars, and add a fuller look to the lips. The collagen isinjected directly into the affected areas.

While bovine collagen has been the undisputed filler of choice for thetreatment of facial wrinkles since injectable skin fillers were firstintroduced, its short-lived results and potential for allergic reactionshas limited its potential. Recently, human bioengineered collagen, whichis collagen derived from human cells, was approved by the FDA fortreating facial wrinkles, acne scarring and lip reshaping. Althoughhuman bioengineered collagen is an improvement over bovine collagenbecause it does not pose an allergy risk, dermatologists continue toseek other improved fillers that can safely and effectively replacehyaluronic acid, one of the primary components lost in aging skin.

Hyaluronic acid is a naturally occurring polysaccharide, which is anormal component of skin. When injected into the skin (typically in agel form), it binds water and pulls it into the skin, increasing skinplumping and volume and filling in larger folds of skin around the mouthand cheeks. One of the main advantages of hyaluronic acid gel is that itdoes not pose an allergy risk for patients and there is no risk oftransmitting animal diseases by injection.

Some commercial forms of hyaluronic acid are Restylane, Hylaform, andHylaform Plus. Restylane and Hylaform do not contain a local anesthetic,and patients are more comfortable when topical or local anesthesia isused before treatment. Currently, the trend is to use a combinedtreatment of hyaluronic acid and collagen to maximize the benefits ofeach filler. An initial injection of collagen can numb the area, give itsupport and structure, and stabilize the skin to prevent bruising. Whenthe hyaluronic acid gel is injected afterward, the patient is numb fromthe collagen injection (reducing the pain) and less likely to bruise,but still receives the benefit of adding volume and water content to theskin. Using these fillers together, two of the major skin componentsthat are lost with skin aging are replaced, can result in a moreyouthful and natural appearance. Juvederm is another form of hyaluronicacid in injectable form for filling facial lines and wrinkles, enhancingthe lips and correcting small facial scars and minor imperfections.Hyaluronic acid is the most popular material used for these purposes andhas, over many years, been demonstrated to be both safe and effective.

One of the recent injectable skin fillers on the horizon ispolymethylmethacrylate, made from a mixture of micronized plasticspheres and bovine collagen. When polymethylmethacrylate is injectedinto the skin, the collagen works by holding the synthetic spheres inplace until it dissipates after injection—leaving the spheres behind to“prop up” the wrinkles. These spheres stimulate the body's ownproduction of collagen, which then forms around the spheres. The mainbenefit of polymethylmethacrylate is its permanence, but it also can beits downfall if not injected properly.

For patients who want results that last longer than collagen but not thepermanent results of polymethylmethacrylate, a new filler known ashydroxyapatite with a methylcellulose vehicle is being studied as aninjectable skin filler. The synthetic compounds used in this fillercontain beads of calcium hydroxyapatite, which is a substance used toreplace missing bones. If not injected properly, the calcium beads couldclump together and result in lumpiness in the treated area.

For example, Radiance (or Radiesse) is one example of a calciumhydroxyapatite filler that is intended to reduce the appearance offacial lines and folds. The product is injectable as is intended to lastyears, as opposed to months. Radiance consists of calciumhydroxylapatite (a derivative of human bone) microspheres mixed into agel form. In many studies, this product has been shown to remain softfor long periods of time when injected into soft tissue, such as facialtissue. Radiance (or Radiesse) particles are not FDA approved forcosmetic applications, but are approved for radiographic tissue markingand vocal fold insufficiency. The composition is manufactured frommicrospheres of calcium hydroxyapatite that are 25 to 45 microns, and upto 150 microns. The particles must be sufficiently large so as to avoidphagocytosis. See U.S. Pat. No. 6,558,612, which also states that thatparticles smaller than 15 microns become engulfed by the cells andremoved from the site by the lymphatic system.

The calcium phosphate particles of this invention may also be used inconjunction with one or more of these skin fillers as a deliveryvehicle, as an adjuvant, or as a separate and distinct skin filler. Aspreviously discussed, any of the above components or a similar componentmay be used as an aesthetic factor in the above example. Those ofordinary skill in the art would be able to determine appropriateconcentration and dosage amounts.

II. Other Dermal Stimulators

Calcium phosphate particles may also be delivered in combination withany other injectable skin treatment or dermal stimulator, which may beused as an aesthetic factor in the above example. For example, poly-Llactic acid is not really considered a skin filler, but a “dermalstimulator” because it stimulates the skin cells to makecollagen—providing a slow correction over time. It is also possible thatthe particles of the present invention will also have a prolongedeffect. Research studies of poly-L lactic acid for FDA approval ofwrinkles are just beginning. One example of a poly-L-lactic acid isSculptra™ (poly-L-lactic acid), which has been used since 1999 under thetrade name New-Fill™. It has been used for restoration and/or correctionof the signs of facial fat loss (lipoatrophy) in people with humanimmunodeficiency virus. Facial fat loss, or lipoatrophy, is the loss offat beneath the skin, which can result in sunken cheeks, indentations,and hollow eyes. Sculptra™ is injected below the surface of the skin inthe area of fat loss. Although not immediate, effects may last up to 2years after the first treatment session.

Cymetra is a another injectable product, but it is derived from humancells. It is micronized (dry powder) injectable form of AlloDerm tissueused to repair or replace inadequate or damaged tissue caused bysurgery, injury, or disease. It also can be used for smoothing deeprhytids, repairing acne scarring, and other facial reconstructiveprocedures. It is injected beneath the skin and replenishes the verysubstance that aging depletes. Furthermore, it stimulates ones owntissues/cells to regenerate into the injected “scaffolding.” It is as ifone is injecting a blueprint beneath the skin directing your own body torepair the skin damaged from aging and the sun. It contains all theelements vital to replace tissue (collagens, elastin, andproteoglycans). Similar to collagen, Cymetra often requires severalinjections to reach a desired result and will require periodicmaintenance injections.

The calcium phosphate particles of this invention may also be used inconjunction with one or more of these dermal stimulators as a deliveryvehicle for any aesthetic factors described above, and specificallygrowth factors, botox, vitamins and minerals, as an adjuvant, or as aseparate and distinct stimulator. As previously discussed, any of theabove components or a similar component may be used as an aestheticfactor in the above example. Those of ordinary skill in the art would beable to determine appropriate concentration and dosage amounts.

III. Topical Treatments

Another embodiment of the invention includes calcium phosphate particlesdelivered in combination with a topical treatment, such as amicrodermabrasion agent or a chemical peel. Peels and microdermabrasiontreatments may greatly improve scars, discolorations, wrinkles,sun-damaged, acne prone and aging skin, and other skin imperfections.Any chemical peel or microdermabrasion agent may be an aesthetic factorin the above example.

Chemical peels use a chemical solution to smooth and improve the textureof the facial skin. Damaged outer layers of skin are removed during theprocess. A chemical peel is usually performed for cosmetic reasons andmay be helpful to those who have wrinkles, blemishes, and uneven skincoloration. Chemical peels may also remove pre-cancerous skin growths,soften acne facial scars, and control acne. TCA (trichloro acetic acid)is a non-toxic chemical that has been used to perform skin peels formany years. The calcium phosphate particles of this invention may serveto reduce the amount of TCA that is required to have the same desiredeffect as TCA alone; the particles may serve to localize the effects ofTCA for a longer time period.

Another skin resurfacing treatment is microdermabrasion, which removessurface dead cells from the skin, and brings forward plump, fresh,healthy cells in conjunction with collagen and elastin tissue.Microdermabrasion is a progressive skin resurfacing treatment thatutilizes a hand piece through which powdered micro-crystals are glidedacross all areas of the face, neck, decollete, back, and/or hands. Thecrystals are then vacuumed up along with the polished skin. Thistechnique delivers a gentle abrasion to help treat acne scarring, sundamaged skin, lighten brown spots, and treat unevenly textured or oilyskin. It can also soften fine lines and wrinkles, decrease theappearance of large pores, and help loosen blackheads.

The crystals may be silica gel crystals, microcrystalline aluminumoxide, alumina crystals, magnesium oxide crystals, sodium bicarbonatecrystals, anti-oxidants, or any other commonly used materials formicrodermabrasion. They may be of any morphology and grit and may be foreither in-home use or for use in a doctor's office only. As previouslydiscussed, any of the above components may be used as an aestheticfactor in the above example, including any other materials that may beused for microdermabrasion. Those of ordinary skill in the art would beable to determine appropriate concentration and dosage amounts.

The calcium phosphate particles of this invention may also be used inconjunction with one or more chemical peels or microdermabrasion agentsas a delivery vehicle, as an adjuvant, or as a separate and distinctmicrodermabrasion agent. As previously discussed, any of the abovecomponents or a similar component may be used as an aesthetic factor inthe above example. Those of ordinary skill in the art would be able todetermine appropriate concentration and dosage amounts.

IV. Delivery Of Vitamins And Minerals

Some skin products deliver vitamins, minerals, and alpha-hydroxy-acidsto the skin, for example, topical vitamin-C, vitamin-E, and vitamin-Aproducts, moisturizers, broad spectrum sunscreens, and alpha-hydroxyacid products. Any skin vitamin, mineral, herbs or other organictreatment intended to enhance the skin's appearance and texture may bean aesthetic factor in the above example. Treatment may be topical orvia injection, into the mesodermal tissues below the skin.

One procedure intended to help deliver topical treatments is the use of“micro-needles” to puncture a layer of the epidermis, which is the mainobstruction to penetration of active ingredients. Once this layer hasbeen breached, the active ingredients in the skin care products canreach into the depths of the skin more effectively than by simplyapplying the products topically. The higher the levels of vitamins thatcan penetrate into the lower layers of the epidermis, the more collagencan be made, allowing natural collagenesis to occur.

As previously discussed, any of the above components or other similarvitamins or minerals or herbs may be used as an aesthetic factor in theabove example. Those of ordinary skill in the art would be able todetermine appropriate concentration and dosage amounts.

V. Vein Treatments

Sclerotherapy is a popular vein treatment option for elimination ofspider veins and varicose veins. These veins typically appear in legs,but similar treatments may be delivered for rosacea or veins that mayappear more pronounced on a patient's face. During the Sclerotherapyprocedure, a sclerosing solution is injected into the vein through amicro-needle. Any sclerosing agent known in the art may be used withthis invention as an aesthetic factor in the above example. Thesclerosing solution causes the vein to blanch (turn white), thengradually to disappear. Sclerotherapy can enhance the appearance oflegs, but can also improve the lower extremity circulation. Thereduction and elimination of such veins allows the blood flow to bere-routed and also helps diminish aching or fatigue associated withthem.

As previously discussed, any of the above components may be used as anaesthetic factor in the above example. Those of ordinary skill in theart would be able to determine appropriate concentration and dosageamounts.

It should also be understood that the activity of the calcium phosphateparticles of the present invention, in addition to being an excellentcarrier of any of the above-described treatments, may also enhance theactivity of the treatments, i.e., by acting as a stimulant or adjuvant.It may also be used to provide a slow release of the composition beingdelivered. The presence of calcium phosphate in the treated tissues mayhelp increase the activity levels the cells, thereby enhancing theactivity of the component to be delivered. Also as discussed above, thecalcium phosphate particles of this invention may also act alone, forexample, they may be delivered as a skin filler in order to lessen theappearance of wrinkles.

If injected, any pharmaceutically acceptable excipient may be used tocarry the particles. If applied topically, the particles may beincorporated into a cream, a gel, an ointment, a lotion, an oil, or anyother acceptable delivery vehicle.

1. A skin filler for treating one or more skin conditions, consistingessentially of: a calcium phosphate particle having a diameter ofbetween about 200 nm to about 4000 nm.
 2. The skin filler of claim 1,wherein the skin filler is adapted to be delivered to a layer of skinvia topical delivery or via injection.
 3. (canceled)
 4. The skin fillerof claim 1, wherein the calcium phosphate particle is smooth without anysurface irregularities larger than 100 nm.
 5. The skin filler of claim1, wherein the calcium phosphate particle is spherical, round, or ovalin shape.
 6. The skin filler of claim 1, wherein the calcium phosphateparticle is coated or has at least a partial layer of a surfacemodifying agent covering the particle.
 7. The skin filler of claim 6,wherein the surface modifying agent is a basic sugar, a modified sugar,an oligonucleotide, a carbohydrate, cellobiose, or polyethylene glycol.8. The skin filler of claim 1, wherein the calcium phosphate particle issmooth or substantially smooth. 9-15. (canceled)
 16. A chemical peel,consisting essentially of: a calcium phosphate particle having adiameter of between about 200 nm to about 4000 nm have an aestheticfactor comprising trichloro acetic acid or other chemical peel agent atleast partially coating the particle or impregnating the particle orboth.
 17. The chemical peel of claim 16, wherein the calcium phosphateparticle is smooth without any surface irregularities larger than 100nm.
 18. The chemical peel of claim 16, wherein the calcium phosphateparticle is spherical, round, or oval in shape.
 19. The chemical peel ofclaim 16, wherein the calcium phosphate particle is smooth orsubstantially smooth.
 20. A microderm abrasion treatments, consistingessentially of a calcium phosphate particle having a diameter of betweenabout 200 nm to about 4000 nm having an aesthetic factor comprisingsilica gel crystals, microcrystalling aluminum oxide, alumina crystals,magnesium oxide crystals, sodium bicarbonate crystals, anti-oxidants, orany other commonly used materials for microderm abrasion at leastpartially coating the particle or impregnating the particle or both. 21.The microderm abrasion treatment of claim 20, wherein the calciumphosphate particle is smooth without any surface irregularities largerthan 100 nm.
 22. The microderm abrasion treatment of claim 20, whereinthe calcium phosphate particle is spherical, round, or oval in shape.23. The microderm abrasion treatment of claim 20, wherein the calciumphosphate particle is smooth or substantially smooth.
 24. The microdermabrasion treatment of claim 20, wherein the injection is intradermal.